The Old Order Amish are a unique closed founder population who are relatively genetically homogeneous, and have very large family sizes and well documented genealogies. Through genome wide linkage analysis, we identified a region of strong linkage to both diastolic (LOD = 4.23) and systolic (LOD = 1.61) blood pressure (BP) on chromosome 2q31-q24. Through our ongoing linkage disequilibrium (LD) mapping and positional candidate gene analyses in the Amish, we have identified a critical region of about 700 kb at 2q32.2 that is strongly associated with BP. Most recently, through finer LD mapping with SNPs in over 1,800 DMA samples from the Framingham Heart Study (FHS), we have localized the BP-associated region to approximately 137 kb in length. The objective of this application is to positionally clone the putative blood pressure gene on chromosome 2q32.2. Aim 1 will utilize a positional candidate gene approach in which sequence variation within all of the ESTs and predicted genes in the region will be identified, genotyped, and association analyses performed in the Amish, and outbred Caucasian and African Americans of the FHS and CARDIA cohorts. Specific Aim 2 will utilize systematic LD mapping through genotype and association analysis of SNPs spaced at 3 - 5 kb. intervals across the critical region in the 3 populations. Specific Aim 3, the "end game", will seek to identify all sequence variation in the associated haplotype block identified in Aims 1 and 2 followed by the iterative process of DNA sequencing, genotyping, and association analysis. Finally, we will test if the most encouraging SNPs (and haplotype) can account for the original linkage in the Amish. Discovery of genes influencing blood pressure will provide (i) critical insights into molecular mechanisms; (ii) new molecular targets for therapeutics; and (iii) blood tests for the early detection of susceptible individuals so that targeted preventative interventions can be instituted. These advances will impact substantially on the quality of life of millions of Americans.